PROJECT SUMMARY The DIAN-TU platform was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop dominantly inherited AD (DIAD). The DIAN-TU trial platform is now fully operational in 6 countries and 24 sites with another 13 countries and 26 sites in start-up. The current DIAN-TU-001 trial will accommodate 11 languages and has three different therapies being tested in secondary prevention (i.e. cognitively normal participants with substantial AD pathology). NIA funding for the DIAN-TU trial platform established the infrastructure and operations for executing clinical trials in DIAD and acknowledged the need for evolution within this platform. The DIAN-TU Primary Prevention Trial is a first of its kind, phase II/III, 4-year randomized, blinded placebo-controlled (1:1) trial in 160 asymptomatic dominantly inherited Alzheimer disease mutation carriers who are more than 15 years before the estimated year of symptom onset (EYO) and have minimal to no A- PiB plaque burden at trial entry. Current trials in asymptomatic individuals target A after pathology is established; these secondary prevention efforts are likely more effective than treating at later more advanced stages, however the most effective approach is to prevent AD pathology from forming. The goal of this proposal is to implement a placebo controlled biomarker endpoint clinical trial targeting amyloid deposition in subjects at risk for DIAD, prior to onset of significant A pathology. In this study, we will test if it is possible to prevent A deposition in DIAD mutation carriers and if doing so will prevent the cascade of pathology associated with AD and, ultimately, dementia in a population that is otherwise certain to get the disease. Regardless of the outcome of this study, it will be highly impactful on the AD field in assessing the ability to prevent amyloidosis and the consequences of doing so at the earliest stages of the AD pathological cascade. If the prevention of A pathology in DIAD is accomplished, it will lay the foundation for the ultimate test of the amyloid hypothesis and provide the best opportunity to prove that dementia in this highly vulnerable population, and possibly in sporadic AD and Down syndrome, can be dramatically modified. Should preventing amyloid pathology from developing have no impact on the course of the disease, particularly in this population, this would direct future research and therapeutics towards other mechanisms and pathologies.